Histological grading of tertiary lymphoid structures correlates with renal impairment and adverse outcomes in ANCA-associated glomerulonephritis

Background Tertiary lymphoid structures (TLS) are organized immune aggregates that develop in non-lymphoid tissues during chronic inflammation and are associated with adverse outcomes in various kidney diseases. Their role in antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis remains poorly characterized. Methods This single-center retrospective study included 74 patients with biopsy-confirmed ANCA-associated glomerulonephritis. Intrarenal TLS were graded from G0 to G4 and dichotomized into low-grade (G0-2, n=37) and high-grade (G3-4, n=37). Clinical, laboratory, histopathological, and immunohistochemical parameters, systemic inflammatory indices, and progression to end-stage renal disease (ESRD) were compared between groups. Renal survival was analyzed using Kaplan-Meier and univariate and multivariate Cox regression to identify independent factors independently associated with ESRD. A prognostic nomogram incorporating these independently associated factors was constructed and internally validated using bootstrap-resampled calibration curves and the C-index. Results High-grade TLS patients exhibited significantly lower estimated glomerular filtration rate (9.3 vs. 21.4 mL/min/1.73 m², p<0.001), higher Birmingham Vasculitis Activity Score (17.0 vs. 14.0, p=0.016), lower complement C3, and higher C-reactive protein, as well as a greater prevalence of crescentic/sclerotic histology (89.2% vs. 21.6%, p<0.001). High-grade TLS biopsies showed increased CD20+ B-cell and CD21+ follicular dendritic cell infiltration, while peripheral blood displayed a higher percentage of CD3+ T cells and an elevated Inflammation Burden Index (IBI). ESRD occurred in 51.4% of high-grade versus 27.0% of low-grade patients (p=0.032). High-grade TLS was associated with worse renal survival (log-rank p=0.021). In multivariate Cox regression, high-grade TLS, lower eGFR, lower complement C3, and sclerotic Berden class were identified as potential independent risk factors for ESRD in this cohort. A nomogram integrating these four predictors showed promising discriminative ability (C-index=0.897) and satisfactory calibration for predicting the probability of ESRD occurrence at 1 year. Conclusions High-grade intrarenal TLS appear to be associated with more severe renal impairment, aggressive histopathology, and poor kidney survival in this ANCA-associated glomerulonephritis cohort. The finding that high-grade TLS may be independently associated with ESRD, together with the exploratory TLS-integrated nomogram, suggests a potential role for TLS grading in risk stratification. However, these preliminary findings warrant validation in larger prospective cohorts before any clinical application can be recommended.